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Short Course Neoadjuvant Radiotherapy Improves Overall Survival in Advanced Rectal Cancer

Carlson, Robert H.

doi: 10.1097/01.COT.0000481200.49401.56
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Results from a Phase III Polish study point to a potential new standard of treatment for patients with advanced rectal cancer, short-course chemoradiation. Patients in the Polish II trial who received five days of neoadjuvant radiation followed by consolidation chemotherapy saw a statistically significant improvement in three-year overall survival compared with patients treated with standard five-week chemoradiation. Results of the multicenter, Phase III study were presented at the 2016 Gastrointestinal Cancers Symposium (Abstract 489).

The study compared neoadjuvant 5x5 Gy and consolidation chemotherapy versus standard preoperative chemoradiation in “unresectable” fixed cT3 cancer with limited movability, or cT4 rectal cancer with threatened resection margin. None had distant metastases.

The experimental treatment resulted in a higher radical resection (R0) rate, the primary study endpoint, and also higher pathological complete response, although the differences were not statistically significant.

And while three-year overall survival was greater for the experimental group, disease-free survival and the cumulative incidence of local failure were not statistically different between the two groups.

But there was a trend toward lower toxicity and lower cost, as well as greater convenience in the experimental arm of the study, the researchers reported.

“The new regimen has similar efficacy but causes fewer side effects and is more convenient for patients. It is also less costly compared to standard chemoradiation, so it may be especially valuable in limited-resource settings,” said first author Lucjan Wyrwicz, MD, PhD, Professor and Chief of the Medical Oncology Unit in the Department of Gastrointestinal Cancer at Maria Sklodowska-Curie Memorial Cancer Centre in Warsaw, Poland, who spoke on behalf of the Polish Colorectal Study Group. Principal investigator is Krzysztof Bujko, MD, PhD.

In a presscast held ahead of the symposium, Wyrwicz said two earlier studies had shown that chemoradiation is of equal efficacy to short course radiotherapy in patients with resectable rectal cancer T3N0-2M0 tumors—Polish I (Br J Surg 2006;93:1216-23) and the Trans Tasman trial (J Clin Oncol 2012;30:3827-33). This new report includes patients with more advanced disease, he pointed out.

The trial included 515 patients recruited in Poland and randomly assigned to the experimental group for a short course of five days of radiotherapy at 5 Gy per day followed by three courses of FOLFOX4 delivered over two days per week in weeks 3, 5, and 7 (261 patients); or to a control group receiving 50.4 Gy delivered in 28 fractions given simultaneously with a regimen of 5-Fu bolus, leucovorin and oxaliplatin (254 patients).

Oxaliplatin use was at the discretion of the patient's physician. By study end, 70 percent of patients had received oxaliplatin. Both groups underwent surgery approximately 12 weeks after starting radiation and six weeks after neoadjuvant chemotherapy.

Wyrwicz said acute toxicity rates were lower in the experimental group compared with controls (74% versus 83%). The major toxicities associated with radiotherapy include inflammation of the rectum, diarrhea, inflammation of the bladder, and local skin radiation response. The rate of patients with grade 3/4 toxicity was identical in the two groups, at 24 percent.

Improved Radical Resection Rate

The primary endpoint, rate of resections with negative margins (R0), was 77 percent in the experimental group versus 71 percent in the control group. Pathological complete response rates were 16 percent versus 11.5 percent, respectively.

With a median follow-up of 35 months, three-year overall survival for the experimental group was 73 percent versus 65 percent for controls; disease-free survival rates were almost identical at 53 percent and 52 percent, respectively; and the cumulative incidence of local failure was 22 percent in the experimental group and 21 percent in the controls.

Wyrwicz said short-course radiotherapy may be a particularly helpful option for patients with advanced rectal cancer with metastases in liver or lungs who are potential candidates to have all sites of disease resected.

“A shorter duration of radiotherapy allows such patients to start chemotherapy to control metastases much earlier,” Wyrwicz said. “This seems to be feasible and also effective in this rare subgroup of patients.”

The study was funded by the Polish Ministry of Science and Higher Education.

Oxaliplatin Not Standard

Smitha Krishnamurthi, MD, an ASCO spokesperson and moderator of the presscast, said the short course of radiation is more popular in Europe than in the U.S., “but these results may lead to increased usage of this method of radiation.

“However, we must keep in mind that chemoradiation in this trial included oxaliplatin, which is not a standard treatment and has been shown to increase toxicity of the regimen,” said Krishnamurthi, Associate Professor in the Department of Medicine-Hematology and Oncology at Case Western Reserve University School of Medicine and leader of the Gastrointestinal Oncology Disease team.

“There were several randomized trials that started before this Polish study started that asked the question, ‘what is the value of adding oxaliplatin to 5-Fu and radiation therapy as adjuvant therapy for rectal cancer?’ And they found it did not increase the efficacy of the radiation but did increase toxicity,” she said. “That's why, when those results came out, the [Polish II] study we discussed today gave participants the option of eliminating the oxaliplatin.”

Wyrwicz explained that the patients in his study were advanced cases with what would have been considered unresectable if surgery were done first.

“At the time the trial started, adding extra chemotherapy sounded reasonable since the aim was to maximize the efficacy of the experimental arm,” he said. “But looking back to the start of this trial, I would not have included oxaliplatin because of the toxicity.”

‘A Lot of Interest’

The study is nonetheless relevant, Krishnamurthi said, since it may be the first study to show the short-course radiation achieving a reduction in tumor. That may have been due to the use of chemotherapy after radiotherapy, she said, but could also be due to the delay in surgery, allowing time for the tumor to shrink.

“There is a lot of interest in incorporating short-course radiation because of its convenience and less expense in treatment of rectal cancer, and some randomized trials of short-course radiotherapy are ongoing that will provide us with more data.”

The 2016 Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association Institute, American Society for Radiation Oncology, American Society of Clinical Oncology, and Society of Surgical Oncology.

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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